SUMMARY This application is for an Administrative Supplement to the parent grant R01NS107442: Mechanisms of axon pathology in ALS, submitted in response to NOT-AG-18-039. Alzheimer?s disease and related dementias (AD/ADRD) are the most prevalent neurodegenerative disorders affecting more than 47 million people worldwide and conveying an ever growing societal and economic burden. AD alone, is estimated to affect 5.7 million Americans in 2018. However, the pathogenic mechanisms underlying the development AD/ADRD remain elusive. Interestingly, emerging evidence indicates that prenylation ? the same post-translational lipid modification of proteins under investigation in our parent R01 ? may also play an important role in the pathogenesis of AD. Prenylation reactions are catalyzed by prenyl transferases that attach isoprenoids, either farnesyl or geranylgeranyl pyrophosphate, to proteins with a characteristic C-terminal motif. The recognition that prenylation can modify the structure and function of many important proteins involved in human diseases has invigorated the interest about its involvement in diseases of the nervous system, and, of particular relevance to this project, in the importance of several targets of prenylation in neuronal loss and synapse plasticity. During the development of our parent project we found that farnesyl transferase and geranylgeranyl transferase-I inhibition by silencing of their common subunit FNTA is sufficient to attenuate NMJ denervation in ALS mice. Based on these results, we hypothesize that viral mediated knockdown of FNTA will inhibit protein prenylation and ameliorate the phenotype of the widely used mouse model of tauopathies. The experimental protocol will encompass different time points because the intent is: (a) to begin the study when cognitive impairment and neuronal loss are still not evident, which is at 4 months; (b) to monitor, longitudinally, the effect of inhibiting protein prenylation on the progression of tau pathology, neuronal loss, and cognitive impairment; and (c) to assess efficacy of intervention at different stages of the degenerative process. Thus, we predict that assessing cognitive impairment bi-monthly from month 4 to month 10 will enable us to compare, with adequate resolution, the beneficial effect of silencing FNTA in rTg4510 mice. The sensitivity of these functional endpoints to experimental modulation of tau pathology will be tested in parallel via the administration of doxycycline from 4 months of age in a subgroup of rTg4510 mice. The premise is that doxycycline will arrest the progression of tau burden and atrophy and thereby contribute to maintaining behavioral capacity at baseline levels. If successful this project could link prenylation and AD/ADRD pathogenesis and have far reaching consequence for the development of new therapeutic strategies.